1. Field of the Invention
The present invention relates to methods for inducing humoral and cellular immune responses against malignant cells and infectious agents. In particular, this invention is directed to methods for producing an integrated immunologic response against tumor cells or infectious agents using immunoconjugates comprising antibodies and anti-idiotype antibodies that mimic an epitope of an antigen that is associated with a tumor or infectious agent. The present invention also is directed to a method for augmenting such an integrated response using immunoconjugates, antibodies, anti-idiotype antibodies and cytokines.
2. Background
One of the major goals of immunotherapy is to harness a patient's immune system against tumor cells or infectious organisms. With regard to cancer therapy, the objective is to direct the patient's immune system against tumor cells by targeting antigens that are associated with tumor cells, but not normal counterparts. Although these tumor associated antigens (TAA) have been difficult to identify, certain tumor cells express antigens that are normally not expressed, or expressed at very low levels, in adult life but present during fetal development. One example of such oncofetal TAA is α-fetoprotein, which is expressed by liver cancer cells. Another oncofetal TAA is the carcinoembryonic antigen (CEA), which is expressed in most adenocarcinomas of entodermally-derived digestive system epithelia, as well as in breast tumor cells and non-small-cell lung cancer cells. Thomas et al., Biochim. Biophys. Acta 1032: 177 (1990).
The administration of anti-idiotype antibodies (Ab2) mimicking TAA represents one of the most promising approaches to cancer immunotherapy. Goldenberg, Amer. J. Med. 94: 297 (1993). Ab2 are antibodies directed against the variable regions of conventional antibodies (Ab1). Since Ab2 and antigen can bind with the same regions of the Ab1-combining site, certain Ab2 (termed “Ab2β” or “internal-image” antibodies) can mimic the three dimensional structure of the nominal antigen. Jerne et al., EMBO J. 1: 243 (1982); Losman et al., Int. J. Cancer 46: 310 (1990); Losman et al., Proc. Nat'l Acad. Sci. USA 88: 3421 (1991); Losman et al., Int. J. Cancer 56: 580 (1994). Individuals immunized with Ab2β can develop anti-anti-antibodies (Ab3), some of which (Ab1′) can bind the nominal antigen.
The antigen mimicry properties of anti-idiotype antibodies have led to the use of Ab2β as surrogate antigens (or idiotype vaccines), when the nominal antigen is not readily available or when the host is tolerant to the nominal antigen. In experimental systems, immunization with Ab2β mimicking certain TAA creates specific immunity to the TAA and protect against subsequent tumor growth. See, for example, Nepom et al., Proc. Nat'l Acad. Sci. USA 81: 2864 (1984); Raychaudhuri et al., J. Immunol. 139: 271 (1987). Similarly, anti-idiotype vaccines have been developed against infectious organisms, such as Streptococcus pneumoniae [McNamara et al., Science 226: 1325 (1984)], hepatitis B virus [Kennedy et al., Science 223: 930 (1984)], Escherichia coli K13 [Stein et al., J. Exp. Med. 160: 1001 (1984)], Schistosomiasis mansoni [Kresina et al., J. Clin. Invest. 83: 912 (1989)], and Moloney murine sarcoma virus [Powell et al., J. Immunol. 142: 1318 (1989)].
Cancer patients receiving an anti-TAA of animal origin will usually produce antibodies to the Ab1 and these anti-immunoglobulin antibodies include Ab2. Herlyn et al., J. Immunol. Methods 85: 27 (1985); Traub et al., Cancer Res. 48: 4002 (1988). The anti-idiotype response also may include the generation of T cells (T2). Fagerberg et al., Cancer Immunol. Immunother. 37: 264 (1993). Moreover, Ab2 may subsequently induce a humoral and cellular anti-anti-idiotypic response, Ab3 and T3, respectively, which may recognize the same epitope as Ab1. Id.
Thus, an opportunity exists to provide an approach to immunotherapy utilizing both humoral and cellular immune systems. The applicant has developed methods to provoke an integrated response against tumor cells, as well as against infectious agents. Furthermore, the applicant has developed methods to amplify the immune cascade.